The work proposed in this application will be a continuation of current research and will be directed towards two chief objectives: First, synthesis and testing of low molecular weight protease inhibitors, and second, clarification of the role of trypsin and trypsin inhibitors in the regulation of pancreatic exocrine function. Based on information already accumulated, it is planned to produce large numbers of new aromatic mono- and diamidines and to evaluate them for their inhibitory effect against trypsin, serum and pancreatic kallikrein and the first component of complement. Furthermore, the compounds will be studied for their stabilizing effect on lysosomes. Animal disease models will be employed to determine the in vivo effectiveness of the inhibitors. The ultimate aim is to arrive at compounds that will be useful in pathologic hyperproteolytic states in man, such as hemolytic reactions, angioneurotic edema, shock and inflammation, and in conditions attributed to lysosomal instability, such as crystal-induced arthritis and rheumatoid arthritis. With respect to the pancreas, it will be investigated how presence of trypsin in the small intestine leads to feedback inhibition of the exocrine pancreas, how trypsin inhibitors interfere with this effect, and whether the trypsinogen activation peptide plays a role in the regulatory mechanism. The suppressive effect of bile duct ligation on pancreatic secretion will also be studied in detail. Additional efforts will be directed towards elucidation of the factors that promote selective increases in pancreactic zymogens after long-term ingestion of trypsin inhibitors, especially as to the requirements for certain molecular configurations of the inhibitors and possible participation of the trypsinogen activation peptide in the reaction pathway. BIBLIOGRAPHIC REFERENCES: Geratz, J. D., Cheng, M.C.-F., Tidwell, R.R.: New aromatic diamidines with gamma-oxyalkane or gamma, omega-dioxyalkane chains. Structure-activity relationships for the inhibition of trypsin, pancreatic kallikrein, and thrombin and for the inhibition of the overall coagulation process. J. Med. chem. 18: 477, 1975.